The causes of liver disease are complex and include chronic viral hepatitis (B,C,D), alcohol, drug-associated hepatotoxicities and metabolic disorders. However, fibrosis leading to cirrhosis and end-stage liver disease is the common pathway for hepatic injury. Rates of fibrotic progression are highly variable, and reflect differences in host response to disease. One host factor, a chemokine receptor named CCR5 may play a central role in modulating hepatic fibrosis, and will be the primary subject of exploration in this study. We will examine the effects of CCR5 deletion mutations (CCR5- ?32) in a large and well- characterized cohort of patients with hemophilia who were followed for up to 18 years in the NIH Multicenter Hemophilia Cohort Studies (MHCS). In addition we will utilize samples derived from a study of HIV-infected patients treated with a unique CCR5/CCR2 inhibitor, Cenicriviroc. In Specific Aim 1 we will characterize the effect of CCR5 on in vivo hepatic fibrogenesis, focusing on both intrinsic (gene polymorphism) and extrinsic (CVC) associated CCR5 blockade. Specific Aim 2 will examine the immune regulatory mechanisms which may affect fibrosis development in relation to CCR5 mutation or blockade using both lymphocytes and liver tissue. Specific Aim 3 will utilize in vivo methods to characterize the effec of CCR5 antagonism on HCV and the immune environment. Using RNAseq and other experimental methods we will determine the pathway(s) involved with modulation of HCV replication and hepatic fibrogenesis. We hypothesize that either host mutation in CCR5 coding genes or pharmacologic blockade will reduce hepatic fibrosis and will attempt to elucidate the mechanism(s) by which this occurs. This study may generate new paradigms for prevention of hepatic fibrosis in those with HIV infection.